Cancer, also known as malignant tumors, is a common disease that seriously threatens the human health. At present, mortality of cancer is still rising, but there lacks effective drugs on treating the common solid tumors. Most existing chemotherapy drugs kill cancer cells through interfering with some aspects in the cell division process, but they do not differentiate cancer cells from normal cells. Therefore, these drugs will also produce side effects while killing cancer cells.
Angiogenesis refers to the new vascular tissues which are generated by the endothelial cells on the basis of the existing vascular bed, thus to provide blood supply to the new tissues which are far away from the existing vascular system. In the physiological state of mature individuals, except during women's menstrual cycle, vascular endothelial cells are in a stable state, without vascular regeneration. The continuous state of angiogenesis is closely related to pathological conditions, such as tumor growth, metastasis, and wound healing.
The angiogenesis process is regulated by a variety of vascular growth regulators (TAFs). At present, more than 20 vascular growth regulators and correlation factors have been isolated and purified. Recently, some factors have been under extensive research, such as vascular endothelial factor (VEGF), transformation growth factor (TGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), angiogenin, grain-colony stimulating factor (GCSF), α-tumor necrosis factor (TNF-α), interleukin-8 (IL-8), proliferin, activators of integrins, hepatocyte growth factor (HGF), etc. The angiogenic inhibitors include thrombospondin, angiostatin, endostatin, etc.
Under the normal condition, there is a balance between angiogenic stimulators and inhibitors. When the angiogenic stimulators are at an up state, while the angiogenic inhibitors are at a down state, the angiogenesis mechanism is “open”, and the tumor vessels regenerate. This is the angiogenesis switch balance hypothesis proposed by Hanahan et al.
The vascular endothelial cell growth factor (VEGF) can be secreted from a variety of tumor cells, and is the major inducer of angiogenesis, so it is at the core position of the tumor angiogenesis. VEGF binds to its receptor tyrosine kinase to achieve the signal transduction in vascular endothelial cells, thus inhibiting the activity of VEGF receptor tyrosine kinase can effectively inhibit the tumor angiogenesis.
VEGF receptor (VEGFR) tyrosine kinase is a promising anticancer target. The compounds that are already in the market or under clinical trials, such as Sutent, Vatalanib succinate (PTK787/ZK222584) and Zactima (ZD6474), all have the ability to inhibit the activity of VEGFR.
There is no report on the synthesis of benzo-triazine and pyridido-triazine and application of triazine derivatives in anti-cancer treatment in current literature.